1. Field of the Invention
The present invention relates to a series of heteroaryl-substituted pyrrole derivatives which have excellent inhibitory activity against the production of inflammatory cytokines such as interleukin (IL)-1, IL-6 and IL-8 and tumor necrosis factor (TNF), particularly IL-1β and TNFα. As a consequence, the compounds of the present invention have valuable anti-pyretic, analgesic, anti-viral and anti-inflammatory activity and are useful in the prophylaxis and treatment of autoimmune diseases such as chronic rheumatism, bone diseases such as osteoporosis and the many other diseases in which the above-described inflammatory cytokines take part. The invention also provides methods and compositions using these novel compounds as well as processes for their preparation.
2. Background Information
Non-steroidal anti-inflammatory drugs (NSAIDs) have been widely used for the treatment and prophylaxis of various inflammatory diseases and in pain relief because they have, as their main pharmacological activity, anti-pyretic, analgesic, and anti-inflammatory activity which is based on their ability to inhibit the biosynthesis of prostaglandin (PG) through the inhibition of cyclooxygenase activity. Another class of compounds commonly used for the tannest of rheumatoid arthritis is tie disease-modifying anti-rheumatic (DMARDs), examples of which include methotrexate and sulphasalazine. This is a wide class of drugs in which the compounds have no common mechanism of action. For the treatment of chronic rheumatism, NSAIDs are used nosotropically and DMARDs are used enotropically. There are a number of problems associated with these classes of drugs. Conventional NSAIDs can induce undesirable side effects including gastointestinal disorders such as gastric ulcers and renal disorders, resulting in difficulties for any patient who has to take such a drug for an extended period of time. DMARDs can also induce undesirable side effects including nausea and diarrhoea and, furthermore, they have not yet been clearly shown to exhibit a stable, long-lasting effect.
A class of active substances generally called cytokines, which are produced in the body by immunocytes, has recently been found. One group of cytokines is known as the inflammatory cytokines and it includes interleukin (IL)-1, IL-6 and IL-8 and tumor necrosis factor (TNF). The inflammatory cytokines have been demonstrated to play a major role in a number of biological processes. These include action as an inflammatory mediator through the stimulation of the arachidonic acid metabolic pathway leading to the production of PG, the migration of leukocytes, the production of acute phase protein, and activation of osteoclasts.
It is believed that the inflammatory cytokines are associated with many diseases including inflammatory diseases and the induction of bone resorption. Due to their mechanism of action, which is different from that of conventional drugs such as those described above, compounds which are able to inhibit the production of inflammatory cytokines are expected to provide an improved new generation of anti-pyretic, analgesic and anti-inflammatory drugs and medicaments for the treatment of autoimmune diseases such as chronic rheumatism, bone diseases such as osteoporosis and the many other diseases in which the above-described inflammatory cytokines are believed to take part.
Compounds which are said to demonstrate inhibitory activity against the production of inflammatory cytokines include various heteroaryl compounds [see, for example, WO 96/21452, WO 97/5877, WO 97/23479 and J. Med. Chem., 39, 3929–3937 (1996)]. Examples of compounds of this type include the following:

There is a need for further compounds having improved activity, pharmacokinetics and safety, and it is this need which is addressed by the present invention. Compounds having the characteristic bicyclic amino group of the compounds of the present invention have been neither disclosed nor suggested in the prior art.